Conformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis

Sarah E. Garnish, Yanxiang Meng, Akiko Koide, Jarrod J. Sandow, Eric Denbaum, Annette V. Jacobsen, Wayland Yeung, Andre L. Samson, Christopher R. Horne, Cheree Fitzgibbon, Samuel N. Young, Phoebe P. C. Smith, Andrew I. Webb, Emma J. Petrie, Joanne M. Hildebrand, Natarajan Kannan, Peter E. Czabotar, Shohei Koide () and James M. Murphy ()
Additional contact information
Sarah E. Garnish: Walter and Eliza Hall Institute of Medical Research
Yanxiang Meng: Walter and Eliza Hall Institute of Medical Research
Akiko Koide: New York University Langone Health
Jarrod J. Sandow: Walter and Eliza Hall Institute of Medical Research
Eric Denbaum: New York University Langone Health
Annette V. Jacobsen: Walter and Eliza Hall Institute of Medical Research
Wayland Yeung: University of Georgia
Andre L. Samson: Walter and Eliza Hall Institute of Medical Research
Christopher R. Horne: Walter and Eliza Hall Institute of Medical Research
Cheree Fitzgibbon: Walter and Eliza Hall Institute of Medical Research
Samuel N. Young: Walter and Eliza Hall Institute of Medical Research
Phoebe P. C. Smith: Walter and Eliza Hall Institute of Medical Research
Andrew I. Webb: Walter and Eliza Hall Institute of Medical Research
Emma J. Petrie: Walter and Eliza Hall Institute of Medical Research
Joanne M. Hildebrand: Walter and Eliza Hall Institute of Medical Research
Natarajan Kannan: University of Georgia
Peter E. Czabotar: Walter and Eliza Hall Institute of Medical Research
Shohei Koide: New York University Langone Health
James M. Murphy: Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Phosphorylation of the MLKL pseudokinase by the RIPK3 kinase leads to MLKL oligomerization, translocation to, and permeabilization of, the plasma membrane to induce necroptotic cell death. The precise choreography of MLKL activation remains incompletely understood. Here, we report Monobodies, synthetic binding proteins, that bind the pseudokinase domain of MLKL within human cells and their crystal structures in complex with the human MLKL pseudokinase domain. While Monobody-32 constitutively binds the MLKL hinge region, Monobody-27 binds MLKL via an epitope that overlaps the RIPK3 binding site and is only exposed after phosphorylated MLKL disengages from RIPK3 following necroptotic stimulation. The crystal structures identified two distinct conformations of the MLKL pseudokinase domain, supporting the idea that a conformational transition accompanies MLKL disengagement from RIPK3. These studies provide further evidence that MLKL undergoes a large conformational change upon activation, and identify MLKL disengagement from RIPK3 as a key regulatory step in the necroptosis pathway.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-22400-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22400-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-22400-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().